Abnormal increase in blood uric acid level, i.e., hyperuricemia is a disease which closely relates to gout, renal dysfunction, urolithiasis, and the like (Shindan to Chiryo, 2002, 90(2), 244-248 and Shindan to Chiryo, 2002, 90(2), 220-224). Also, in organ transplantation (Ren. Fail. 2002 May; 24(3): 361-7) and chemotherapy of cancers (Am. J. Health Syst. Pharm. 2003 Nov 1; 60(21): 2213-22), it is known that serum uric acid level is remarkably increased and renal dysfunction is induced (tumor lysis syndrome and the like). The therapeutic drugs for hyperuricemia are roughly divided into uric acid-excretion accelerators and uric acid-synthesis inhibitors. However, since the action is reduced in the uric acid-excretion accelerators when renal function decreases, allopurinol (Nippon Rinsho, 1996 Dec; 54(12): 3364-8 and Nippon Rinsho, 2003; 61, Suppl. 1: 197-20) which is a uric acid-synthesis inhibitor is suitably used for patients having decreased renal function (Guideline for therapy of hyperuricemia/gout, Japanese Society of Gout and Nucleic Acid Metabolism, Therapeutic Guideline 2002). Xanthine oxidase is an enzyme directing biosynthesis of uric acid, and xanthine oxidase inhibitors which inhibit the enzyme is effective, as uric acid-synthesis inhibitors, for therapy of hyperuricemia and various diseases attributable thereto. Allopurinol employed in clinical use is only one xanthine oxidase inhibitor which is in practical use, at present.
On the other hand, xanthine oxidase is known to have a role as an active oxygen-producing enzyme (Drug Metab. Rev. 2004 May; 36(2): 363-75). Active oxygen is a exacerbation factor of morbid conditions, which causes DNA and cell damage and also induces inflammatory cytokine production (Free Radic. Biol. Med. 2001 May 15; 30(10): 1055-66). For example, it is known that active oxygen deeply participates in autoimmune and inflammatory diseases such as ulcerative colitis and Crohn's disease (Scand. J. Gastroenterol. 2001 Dec; 36(12): 1289-94) and ischemic reperfusion disorder (Biochem. Biophys. Res. Commun. 2004 Mar 5; 315(2): 455-62). Furthermore, recently, in diabetic kidney diseases (Curr. Med. Res. Opin. 2004 Mar; 20(3): 369-79), heart failure (J. Physiol. 2004 Mar 16; 555(Pt 3): 589-606, Epub 2003 Dex 23), cerebrovascular disorder (Stroke, 1989 Apr; 20(4): 488-94), and the like, it is suggested that active oxygen participates in as one of exacerbation factors. Moreover, in diabetic retinopathy, it is known that an increase in vascular endothelial growth factor (VEGF) in the vitreous body deeply participates in morbid condition and an increase in expression of VEGF through oxidation stress occurs under morbid conditions (Curr Drug Targets. 2005 Jun; 6(4): 511-24). Since a xanthine oxidase inhibitor inhibits production of active oxygen, it is effective in treatment of these diseases. Actually, it has been reported that allopurinol is effective in ulcerative colitis (Aliment. Pharmacol. Ther. 2000 Sep; 14(9): 1159-62), angiopathy involved in diabetes (Hypertension, 2000 Mar; 35(3): 746-51), and chronic heart failure (Circulation, 2002 Jul 9; 106(2): 221-6) in human.
As above, although allopurinol which is a xanthine oxidase inhibitor is reported to have effectiveness for various diseases, severe adverse effects such as Stevens-Johnson syndrome, toxic epidermal necrolysis, hepatopathy, and renal dysfunction have been reported (Nippon Rinsho, 2003; 61, Suppl. 1: 197-201). As one cause thereof, it is pointed out that allopurinol has a nucleic acid-like structure and inhibits pyrimidine.metabolic pathway (Life Sci. 2000 Apr 14; 66(21): 2051-70). Accordingly, it is highly desired to develop a highly safe and highly effective xanthine oxidase inhibitor having a non-nucleic acid structure.
Hitherto, compounds having xanthine oxidase- inhibitory activity have been reported. For example, as xanthine oxidase inhibitors, there have been reported phenyl-substituted azole compounds such as 2-phenylthiazole derivatives (Patent Documents 1, 2, and 3), 3-phenylisothiazole derivatives (Patent Documents 4 and 5), 3-phenylpyrazole derivatives (Patent Documents 6, 7, and 8), 2-phenyloxazole derivatives (Patent Document 9), and 2-phenylimidazole derivatives (Patent Document 9).
On the other hand, it is described that a compound represented by the following formula (II) has a uric acid-excreting action and is useful for therapy of hyperuricemia (Patent Document 10):
wherein A represents an oxygen atom, a sulfur atom, or a vinylene group, B represents an oxygen atom, a nitrogen atom, —(CH2)n — (where n is 0 or 1), or a carbonyl group, R1 represents a hydrogen atom, a lower alkyl group, or the like, R2 represents a lower alkyl group, a hydroxyl group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, a cyano group, a tetrazole group, or the like, R3 represents a hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group, or a lower aminoalkoxy group, R4 represents a nitro group, a cyano group, a halogen atom, a trifluoromethyl group, or the like; see the publication for further information.
In the publication, 2-phenylthiophene derivatives having a carboxyl group or a tetrazole group in the thiophene ring are disclosed (Compound Nos. 75 and 77). These compounds have only a cyano group as a substituent on the phenyl group. Moreover, there are neither disclosure nor suggestion of the xanthine oxidase-inhibitory action and uric acid-synthesis inhibitory action in the publication.
Moreover, it is suggested that a compound represented by the following general formula (III) has an adjuvant arthritis-inhibitory action and is effective for rheumatoid arthritis (Patent Document 11):
wherein X represents a halogen atom, lower alkoxy, or the like, Y represents a hydrogen atom or a lower alkyl group, R represents a hydrogen atom or a lower alkyl group, and a dotted line means that the bond in the position may be a double bond; see the publication for further information.
In addition, it is suggested that a compound represented by the following formula (IV) has an antirheumatic action based on cytokine production inhibition and is effective for treatment of diseases based on immunodeficiency (Non-Patent Document 1):
(there is disclosed eight compounds wherein X is a hydrogen atom, Cl, or Br and R is a hydrogen atom or a methyl or ethyl group).
However, in any of Patent Document 11 and Non-Patent Document 1, there are neither disclosure nor suggestion of the xanthine oxidase-inhibitory action and uric acid- synthesis inhibitory action.
Patent Document 1: WO92/09279
Patent Document 2: JP-A-2002-105067
Patent Document 3: WO96/31211
Patent Document 4: JP-A-57-85379
Patent Document 5: JP-A-6-211815
Patent Document 6: JP-A-59-95272
Patent Document 7: WO98/18765
Patent Document 8: JP-A-10-310578
Patent Document 9: JP-A-6-65210
Patent Document 10: JP-A-2000-1431
Patent Document 11: JP-A-2-193990
Non-Patent Document 1: Bioorganic & Medicinal Chemistry, Britain, 2003, Vol. 11, p.4729-4742